PROJECT SUMMARY Hodgkin lymphoma (HL) outcomes in PLWH in South Africa (S.A.) are inferior to those in HIV(-) patients, although outcomes compare favorably in clinical trials. Advanced stage disease and consistent EBV-association are well recognized in PLWH. In S.A., at the time of diagnosis, some PLWH are in such poor clinical condition that they are not treated. Diagnostic delays contribute to late presentations, as HL diagnoses require surgical biopsies for a definitive pathologic evaluation. Resources and infrastructure in S.A. are limited in this regard. To better understand disparate outcomes in PLWH in standard-of-care settings, we propose a prospective observational study of HIV(+) and HIV(-) HL in S.A. (Aim 1). Performance status (PS), organ function, clinical stage, tumor histological subtype, EBV association, and mutational landscape will all be assessed, as will chemotherapy regimen, response to treatment, and cause of death, as determined by a minimally invasive autopsy in consenting participants. Since tuberculosis (TB) is the leading cause of death in PLWH in S.A., the symptoms of which mimic HL, HL patients are often empirically treated and repeatedly tested for TB before excisional biopsies are pursued. A high co-infection rate coupled with immunosuppressive chemotherapy may lead to TB progression in PLWH during therapy, and may contribute to ultimate mortality. Therefore, Aim 1 will also have a major focus on the contributions of TB. The results of this study will lead to a better understanding of the roles that PS, organ function and TB have in HL prognosis in PLWH, as well as aspects of the EBV association and the mutational features. The near uniform association of EBV in HIV(+) HL may aid in the recognition of HL in PLWH via a non-invasive plasma EBV test that can identify patients needing urgent excisional biopsy. To explore this possibility, we propose to develop a diagnostic algorithm (Aim 2A) in a discovery cohort of PLWH with HL and without malignancy. EBV DNA will be assessed along with additional plasma markers to increase specificity. The optimal combination of markers will be used to develop an algorithm that will be tested in a validation cohort of high risk PLWH (Aim 2B). Baseline PS and organ function will be obtained, and a rigorous yearlong follow-up will ensure accurate classification of persons with lymphoma. In those who are diagnosed with HL or other lymphoma, PS and organ function will be re-assessed. Participants who experience a marked decline in these measures, to the point that they do not receive standard chemotherapy, will be considered potential ?lives saved? if the diagnostic algorithm could be applied clinically. We note that much of the infrastructure needed to implement the molecular techniques is available in S.A., and that our South African collaborators have a track record of introducing sophisticated molecular diagnostics for TB to the entire country. 1